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Is there a room for immune checkpoint inhibitors in early stage non-small cell lung cancer?

ABSTRACT: Early non-small cell lung cancer (NSCLC) represents 16% of all new NSCLC at diagnosis with a 5-year survival rate of about 60%. Surgical intervention and adjuvant platinum-based chemotherapy represent the cornerstone treatments, but no significant advances have been achieved since several decades in term of relapse rate reduction or survival improvement. Immunotherapy represents an appealing strategy considering the acceptable toxicity pro?le but, despite the awesome changing recently introduced in the locally advanced and metastatic setting, its role in early NSCLC is not clear yet. In the past few years, two strategies have been investigated to improve the early NSCLC outcomes eliciting the anti-tumour immune response: tumour vaccines and adoptive cellular therapies. However, none of them provided convincing results. Preclinical and clinical data supported the prognostic role of immune checkpoints in resected NSCLC even if they did not show a clear predictive value for adjuvant treatment. However, some preliminary data about safety and efficacy of neo-adjuvant immune checkpoint inhibitors encourage further investigation of their potential role as monotherapy or as part of a multimodal strategy. Then, even if no significant progress has been done in early NSCLC treatment until today, checkpoint inhibitors can open the door to a new strategy in this setting.

SUBMITTER: Gobbini E

PROVIDER: S-EPMC5994500 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Is there a room for immune checkpoint inhibitors in early stage non-small cell lung cancer?

Gobbini Elisa E Giaj Levra Matteo M

Journal of thoracic disease 20180501 Suppl 13

Early non-small cell lung cancer (NSCLC) represents 16% of all new NSCLC at diagnosis with a 5-year survival rate of about 60%. Surgical intervention and adjuvant platinum-based chemotherapy represent the cornerstone treatments, but no significant advances have been achieved since several decades in term of relapse rate reduction or survival improvement. Immunotherapy represents an appealing strategy considering the acceptable toxicity proﬁle but, despite the awesome changing recently introduced ...[more]

PMID: 29951294

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Project description:There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15-30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or to either programmed cell death-1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.

Project description:Histological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKIs) is a well-described phenomenon. Whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPIs) in non-SCLC (NSCLC) is uncertain. Hence, tissue biopsies are not universally recommended at progression of NSCLC on ICPIs, unlike TKIs. We report a case of a woman in her mid-60s with a 35 pack-years tobacco history and stage IV squamous cell lung carcinoma with no targetable genomic alterations, whose disease progressed within 4 months of first line carboplatin/gemcitabine therapy. Her treatment was switched to second line nivolumab monotherapy which resulted in sustained partial response lasting 21 months. She subsequently developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC. Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed near-identical tumor profiles. Her disease responded to next line carboplatin/etoposide, though lasting for only 10 months. She died 14 months after detection of neuroendocrine transformation of her NSCLC. We performed a systematic review of the literature to identify similar cases of NSCLC-to-small cell transformation on ICPIs. Nine patients, including our index case, were identified, with seven (77.8%) on nivolumab and two (22.2%) on pembrolizumab monotherapy. Median survival time since small cell transformation was 13.0 months (95% CI 2.0 to 16.0). Using our patient case as a framework, we further discuss the lack of consensus criteria to distinguish small cell transformation from de novo metachronous SCLC. Histological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC. Repeat tissue biopsies should be considered at the time of progression, similar to oncogene-directed therapies. Prospective larger studies are warranted to further characterize NSCLC-to-small cell transformation on ICPIs using molecular fingerprinting with paired tumor genomic profiles, evaluation of neuroendocrine features at baseline and consideration of initial response.

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Is there a room for immune checkpoint inhibitors in early stage non-small cell lung cancer?

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Is there a room for immune checkpoint inhibitors in early stage non-small cell lung cancer?

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